Nearly every tissue in the body produces prostaglandins. No other autocoids or hormones show more numerous or diverse effects than prostaglandins. Due to rapid degradation which is most commonly caused by enzymes in the blood and lungs, the effective life of most prostaglandins is only about 3 to 10 minutes.
Prostaglandins including prostacyclin, a prostaglandin analog produced by the body and is implicated in maintaining proper function of blood vessels. Natural prostacyclin is inherently unstable, with an effective life of less than about six minutes. Prostaglandins including prostacyclins appear to act in three ways to keep blood vessels functioning properly, 1) they dilate blood vessels, where necessary, enabling proper blood flow ; 2) they prevent platelet aggregation thereby reducing its obstructive effects on blood vessels; and 3.) it contributes to regulation of proliferation of smooth muscle cells surrounding the vessels, which otherwise would constrict the vessels and further obstruct blood flow. These physiological effects of prostaglandins have been shown to provide therapeutic benefits in the treatment of congestive heart failure.
Congestive heart failure, regardless of its etiology, is characterized by a weakness of the myocardial tissue of the left and/or right ventricles of the heart and the resulting difficulty in pumping and circulating blood to the systemic and/or pulmonary systems. Myocardial tissue weakness is typically associated with circulatory and neurohumoral changes which result in a failure to deliver sufficient blood and oxygen to peripheral tissues and organs. Some of the resulting changes include higher pulmonary and systemic pressure, lower cardiac output, higher vascular resistance and peripheral and pulmonary edema. Congestive heart failure may be further expressed as shortness of breath either on exertion, at rest or paroxysmal nocturnal dyspnea. If left untreated, congestive heart failure can lead to death.
Prostaglandins have been shown to be useful for treating congestive heart failure in humans because of the positive effects generated by such compounds on blood flow through the prevention and reduction of undesirable constriction in blood vessels through vasodilation and anti-platelet effects on the blood. See, for example, Olschewski et al.: Inhaled iloprost to treat severe pulmonary hypertension, Ann. Intem. Med. 132:435-43 (2000); Sueta et al.: Safety and efficacy of epoprostenol in patients with severe congestive heart failure, Am. J. Cardiol. 75:34A-43A (1995); Kerins et al.: Prostacyclin and prostaglandin El: molecular mechanisms and therapeutic utility, Prog. Hemost. Thromb. 10:307-37 (1991); Montalescot et al.: Prostacyclin (epoprostenol) has a positive inotropic effect in patients with severe heart failure, European Heart Journal 18:292 (1997); Pacher et al.: Prostaglandin E1 infusion compared with prostacyclin infusion in patients with refractory heart failure: effects on hemodynamics and neurohumoral variables, J. Heart Lung Transplant 16:878-81 (1997); Patterson et al.: Acute hemodynamic effects of the prostacyclin analog 15AU81 in severe congestive heart failure, Am. J. Cardiol. 75: 26A-33A (1995); and Prostacyclin: basic principles and clinical application in congestive heart failure and primary pulmonary hypertension. Proceedings of a symposium. Bolgna, Italy, November20, 1993. Am. J. Cardiol. 75:1A-73A (1995). However, many prostaglandin and analogs thereof including prostacyclin, have very short effective lives, and provide relief for a short duration, before re-administration is required. Accordingly, any treatment using such prostaglandins would require continuous and sustained administration to provide effective therapy for the patient. It has been suggested that the short effective life of prostaglandins can actually place a stress on the heart by the rapid change in the vessels to facilitate blood flow. To date, the use of prostaglandins and analogs thereof has been severely limited in the treatment of congestive heart failure because of chemical instability, short effective life and limited effective modes of administration.
The short effective life of prostaglandins is due to a) rapid deactivation of the active groups of the molecules by enzymes, and b) their low molecular weight which makes them easily cleared or excreted from the body.
Prostaglandins have active sites typically in the form of hydroxyl and carboxyl groups. Enzymes can rapidly deactivate the active groups thereby rendering the compound ineffective. To overcome the problem, continuous infusion or frequent administration of high doses of prostaglandins have been employed to maintain therapeutically effective levels of the compound in the patient. Such dosage regimens, however, are disadvantageous because the treatment is expensive and there is a relatively high possibility of unwanted side effects including a possible increase in stress on the heart. Some of the side effects include nausea, swelling, gastrointestinal upset, jaw pain, rash, and headaches. In some patients severe adverse reactions have required discontinuing of treatment.
Numerous prostaglandins and analogs thereof such as prostacyclin have been prepared with the goal of discovering pharmaceutically acceptable agents that offer increased stability, a greater range of modes of administration, more effective activity and/or longer effective life. Investigators have sought prostaglandins and analogs thereof which can be effectively delivered orally to provide a less invasive and more convenient medical treatment. Current oral forms of prostaglandins and analogs thereof typically have an effective life of only up to about 1.5 hours and in some cases only a few minutes. The short effective life requires the patient to undertake frequent dosing, and therefore makes administration problematical for the patient, especially those suffering from chronic disease.
Conjugating biologically-active substances such as proteins, enzymes and the like to polymers has been suggested to increase the effective life, water solubility or antigenicity of the active substance in vivo. For example, coupling peptides or polypeptides to polyethylene glycol (PEG) and similar water-soluble polyalkylene oxides (PAO) is disclosed in U.S. Pat. No. 4,179,337, the disclosure of which is incorporated herein by reference. See also, Nucci M., Shorr R G L, and Abuchowski A., "Advanced Drug Delivery Reviews", 6:133-151: 1991; Harris J M (ed.); and "Polyethylene Glycol Chemistry: Biotechnical and Biomedical Application", Plenum Press, NY, 1992. Conjugates are generally formed by reacting a therapeutic agent with, for example, a several fold molar excess of a polymer which has been modified to contain a terminal linking group. The linking group enables the active substance to bind to the polymer. Polypeptides modified in this manner exhibit reduced immunogenicity/antigenicity and tend to have a higher effective life in the bloodstream than unmodified versions thereof.
To conjugate polyalkylene oxides with an active substance, at least one of the terminal hydroxyl groups is converted into a reactive functional group. This process is frequently referred to as "activation" and the product is called an "activated polyalkylene oxide." Other substantially non-antigenic polymers are similarly "activated" or "functionalized."
The activated polymers are reacted with a therapeutic agent having nucleophilic functional groups that serve as attachment sites. One nucleophilic functional group commonly used as an attachment site is the .epsilon.-amino groups of lysines. Free carboxylic groups, suitably activated carbonyl groups, oxidized carbohydrate moieties and mercapto groups have also been used as attachment sites.
Biologically active polymer conjugates can be formed having hydrolyzable bonds (linkages) between the polymer and the parent biologically-active moiety to produce prodrugs (where the parent molecule is eventually liberated in vivo). Several methods of preparing prodrugs have also been suggested. Prodrugs include chemical derivatives of a biologically-active parent compound which, upon administration, will eventually liberate the active parent compound in vivo. Prodrugs are advantageous because they enable modification of the onset and/or duration of action of a biologically-active compound in vivo. Prodrugs are often biologically inert or substantially inactive forms of the active compound. The rate of release of the active drug is influenced by several factors including the rate of hydrolysis of the linker which joins the biologically active compound to the prodrug carrier (e.g polymer).
Although prostaglandins and analogs thereof such as prostacyclin hold much promise as therapeutic agents, there is a need to a) improve the stability of such compounds, b) extend the effective life of the compounds to provide a more effective continuous level of the therapeutic agent in the patient to thereby minimize stress on the heart and c) enable the compounds to be administered in a more patient friendly dosage regimen than is currently available.
It would therefore be a significant advance in the art of drug therapy, especially for the treatment of congestive heart failure, if prostaglandins and analogs thereof and compositions employing the same can be developed which have improved stability, an effective life of sufficient duration to enable administration at a reasonable frequency, with less risk of heart stress from rapid changes in the levels of the therapeutic agents and in a more patient-friendly manner than current therapies employing prostaglandins and analogs thereof.